Drug-induced neutropenia associated with anti-neutrophil cytoplasmic antibodies (ANCA): possible involvement of complement in granulocyte cytotoxicity

Abstract

SUMMARY Although antineutrophil antibodies are thought to be involved in drug‐induced neutropenia, neither the precise mechanisms nor the particular antigens on the neutrophil surface have yet been clarified. Recently, we examined a patient with Graves’ disease who developed antineutrophil cytoplasmic antibodies (ANCA) after propylthiouracil treatment and exhibited neutropenia. Because several target antigens of ANCA are expressed on the surface of neutrophils, it was suggested that ANCA might contribute to neutropenia. The patient’s serum bound specifically to neutrophils and HL‐60 cells differentiated into granulocytes, and lysed the HL‐60 cells via a complement‐mediated mechanism. Furthermore, two representative ANCA antigens, proteinase 3 and myeloperoxidase, significantly inhibited both the binding and cytotoxicity of the serum. Finally, tumour necrosis factor‐α, which is known to up‐regulate cell surface expression of several ANCA antigens, enhanced both the binding and cytotoxicity of the serum. These findings suggest that ANCA induced by propylthiouracil contributed to leucopenia through a complement‐mediated mechanism.

Sudden Onset Agranulocytosis and Hepatotoxicity after Taking Methimazole

“…This data suggests an immune-mediated mechanism rather than direct toxic effects of the drug, but the precise mechanisms have not been clarified (3,18). Several studies have reported that antineutrophil cytoplasm antibodies (ANCA) might contribute to propylthiouracil-(PTU) induced agranulocytosis but these have not been observed in MMI therapy (18,19).…”

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

“…PTU-induced autoimmune disease was known as PTU-induced lupus-like syndrome, PTU is also known as a trigger for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Recently, complement-mediated cytotoxicity was postulated as a mechanism of PTU-induced ANCA-positive neutropenia [9]. ANCA specific for proteinase 3 (PR3) and myeloperoxidase (MPO) are associated with necrotizing vasculitis, and ANCA-activated neutrophils contribute to oxidative and proteolytic damage of blood vessels [10].…”

“…ANCA specific for proteinase 3 (PR3) and myeloperoxidase (MPO) are associated with necrotizing vasculitis, and ANCA-activated neutrophils contribute to oxidative and proteolytic damage of blood vessels [10]. Priming (TNF-alpha)-induced translocation of PR3 and MPO to the cell surface may induce cytotoxicity [9]. ANCA-associated vasculitis and ATD-associated ANCA-positive patients in Belgrade were reported [11].…”

The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis

“…Therefore, it may affect the microenvironment of bone marrow and inhibit the generation and differentiation of pluripotent hematopoietic stem cells. The immunological reactions include the immunoglobulin (Ig) E-mediated hypersensitivity reaction, drug-induced IgG and IgM responses, and antineutrophil cytoplasm antibodies (ANCA) associated immune injury, which might contribute to agranulocytosis [1,7,[12][13]. Bone marrow characteristics may be valuable in revealing the tion of the 33 cases, there were 15 cases with bone marrow active proliferation, 3 cases with hyperplasia and 2 cases with hypoplasia in type I, while 3 cases with hyperplasia and 10 cases with active proliferation were indentified in type II.…”

“…Therefore, hypoplasia with decreased or absent of precursor cells is the common characteristics of drug toxicity [10]. However, ATD related immune complexes may selectively react on antigen targets on the surface of mature granulocytes or granulocyte progenitor cells [6,12]. The hematopoietic function of bone marrow is not completely inhibited.…”